Cancer is the leading cause of death among the Japanese, and anti-cancer agents are being constantly developed. In particular, anti-cancer agents that are capable of inhibiting cancer cell invasion, metastasis, and other symptoms are being developed.
Generally, many anti-cancer agents cause serious side effects, and to meet the market's needs, it is time to develop anti-cancer agents that cause few side effects. Although molecularly targeted drugs, such as antibody drugs, in particular, are drawing attention, their manufacturing costs are high, and the drug prices do not decrease, which imposes a great burden on patients in terms of costs.
Patent Literature (PTL) 1 discloses a pyrazolidinedione derivative as a DOCK inhibitor. This compound is known to have an inhibitory effect on the Rac-GDP-to-Rac-GTP conversion activity (in this specification, this activity is sometimes referred to as “GEF activity”) of DOCK1 (or DOCK180), DOCK2, and DOCK5, which are members of the DOCK-A subfamily.
In view of DOCK2 being expressed specifically in immune cells, PTL 1 confirms that pyrazolidinedione derivatives (e.g., CPYPP) inhibit chemokine-induced migration of immune cells (T cells, B cells), and discloses that such derivatives can be used as an active ingredient for treating immune diseases. The document also confirms that pyrazolidinedione derivatives have an inhibitory effect on cancer cell invasion and cancer cell anchorage-independent growth, and discloses that such derivatives can be used as an anti-cancer agent.
DOCK1 and DOCK5 have already been known to ubiquitously express in the whole body. Regarding DOCK1, in particular, a mechanism has been reported recently in which Rac activated by the GEF activity of DOCK1 regulates HER2-mediated breast cancer metastasis (Non-Patent Literature (NPL) 1). This document also reports that the CPYPP mentioned above inhibits the Rac activation and cancer cell migration.
DOCKs are known to be involved in ruffle formation, which serves as an index of morphological changes in cell migration. Two types of ruffles, i.e., peripheral ruffles and dorsal ruffles, have been clarified to be present in ruffle formation. It has also been clarified that the former is regulated by both DOCK1 and DOCK5 while the latter is regulated by DOCK1 alone (NPL 2).